Synthesis of Pyridines and Pyrido[2,3-d]pyrimidines by the Lewis Acid Catalysed Bohlmann-Rahtz Heteroannulation Reaction

Abstract

Lewis acids catalyse the Bohlmann-Rahtz heteroannulation reaction to generate highly functionalised pyridines from enamino esters and alkynones in a single synthetic step. Of the catalysts studied, ytterbium(III) trifluoromethanesulfonate and zinc(II) bromide are the two most efficient for the synthesis of pyridines and pyrido[2,3-d]pyrimidines, from ethyl b-aminocrotonate or 2,6-diaminopyrimidin-4-one respectively, in up to 94% yield.The synthesis, reactions and biological properties of pyridine-containing derivatives is an ever-expanding subject in heterocyclic chemistry. This structural motif may be found in a large number of pharmaceutical agents, 1 as a pharmacophore of considerable historical importance, and so new methods for their preparation have received a great deal of attention in the literature. The synthesis of pyridine 4 in two steps by Michael addition-cyclodehydration of ethyl b-aminocrotonate 1 and but-3-yn-2-one 2 was first reported by Bohlmann and Rahtz in 1957 and proceeds via aminoheptadienone intermediate 3, that is isolated and heated to high temperature to facilitate the cyclisation (Scheme 1). 2 Since its discovery, it is noteworthy that very few applications of this reaction have appeared in the literature. A synthesis of the modified core of promothiocin antibiotics has been reported, 3 using the Bohlmann-Rahtz heteroannulation reaction for the preparation of clusters of pyridine-containing heterocycles that were elaborated to the natural product. 4,5 Scheme 1In order to improve the utility of the Bohlmann-Rahtz pyridine synthesis, and facilitate the transfer of this technology to the solid phase, we demonstrated that this method, which traditionally requires high cyclodehydration temperatures, may be affected in a single synthetic step for the synthesis of tetrasubstituted pyridines 5 using either acetic acid or Amberlyst 15 ion exchange resin at 50°C (Scheme 2). 6 These modified conditions were for the most part unsuccessful for the synthesis of pyrido[2,3-d]pyrimidine 7 from 2,6-diaminopyrimidin-4-one 6, although the traditional two-step Bohlmann-Rahtz heteroannulation reaction, 2 that proceeds by Michael addition in DMSO and subsequent cyclodehydration at 180°C, proved to be a highly expedient method for the preparation of these heterocycles (Scheme 3). 7 Scheme 2 Scheme 3In order to establish a new one-step general method for the synthesis of pyridines and pyrido [2,3-d]pyrimidines that avoids the use of high temperatures, we have investigated the use of Lewis acid catalysts in the Bohlmann-Rahtz heteroannulation reaction. To test the validity of this approach, Bohlmann-Rahtz intermediate aminodienone 3 was prepared by standard procedures 2 and treated with a Lewis acid to see if cyclodehydration could be conducted at a lower reaction temperature. The use of BF 3 ×OEt 2 failed to generate even a trace of pyridine 4, whereas zinc(II) bromide (15 mol%) or ferric chloride (10 mol%) in dichloromethane did promote the cyclisation. Full conversion was achieved when a solution of aminodi...

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